Project Summary Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that affects more than 2.5 million people worldwide with an unknown etiology. People with MS can experience relapsing-remitting or progressive forms of disease, with the latter associated with cortical atrophy and cognitive decline. While MS is classically regarded as a disease of the white matter, recent evidence suggests that there is significant myelin loss in the gray matter of patients with MS. Cortical lesions are common in early MS and their increasing abundance during late stages of MS suggests that they may be an important therapeutic target. B cells are directly implicated in MS pathology, with recent evidence implicating IgG-mediated demyelination in pathology and the effectiveness of anti-B cell therapies in treatment of MS. However, mechanisms regulating myelin injury and repair in cortical lesions are incompletely understood. Progress in the understanding of MS has been constrained by the paucity of animal models that recapitulate hallmarks of the disease and inability to detect the dynamics of cortical demyelination in living patients. To overcome these limitations, we have developed both a novel mouse model of MS antibody-dependent demyelination and approaches to visualize myelin, oligodendrocytes, and their precursors in the living mouse brain. Here we propose to capitalize on these innovative approaches to discern the dynamics of demyelination and repair myelin in cortical lesions. The objectives of this proposal are: 1) Develop and evaluate a new model of antibody-mediated MS cortical demyelination and 2) Elucidate the mechanisms underlying remyelination in cortical lesions. This proposal breaks new ground by developing novel approaches to understand the mechanisms underlying cortical lesions that characterize MS and provide an in vivo mouse model platform that will allow for the evaluation of new therapeutic candidates for MS.